{"doi":"10.1101/2025.05.08.652716","title":"Profiling metabotropic glutamate receptor 7 expression in Rett syndrome: consequences for pharmacotherapy","abstract":"Abstract We have reported that levels of metabotropic glutamate receptor 7 (mGlu 7 ) are dramatically decreased in brain samples from Rett syndrome patients carrying truncation mutations in the Methyl-CpG Binding Protein 2 ( MECP2 ) gene. Additionally, we identified decreases in mGlu 7 levels in Mecp2 +/- female mice and demonstrated that administration of a positive allosteric modulator (PAM) with activity at mGlu 7 corrected deficits in cognitive, social, and respiratory domains. Here, we expanded our studies to a larger cohort of RTT samples covering a range of mutations and evaluated expression of the three widely expressed group III mGlu receptors (mGlu 4,7 and 8 ). We found significant decreases in mGlu 7 , but not mGlu 4 or mGlu 8 , mRNA expression across this larger cohort; additionally, we identified a previously unknown and robust correlation in the expression of mGlu 4 and mGlu 8 in control individuals. Stratification of RTT patients into individuals with mutations that are clinically correlated with severe versus mild disease revealed statistically significant decreases in mGlu 7 expression only in patients with mutations that induce more severe symptoms. We then administered the PAM VU0422288 to mice modeling the mild R306C mutation ( Mecp2 R306C/+ ) and found a significant reduction in apneas induced by VU0422888 administration despite no decreases in mGlu 7 expression in the brainstem or cortex. These results provide the first evidence of potentially broad utility for mGlu 7 PAMs in reducing apneas in RTT patients.","journal":"bioRxiv (Cold Spring Harbor Laboratory)","year":2025,"id":557846,"datarank":0.10397207708399181,"base_score":0.6931471805599453,"endowment":0.6931471805599453,"self_citation_contribution":0.10397207708399181,"citation_network_contribution":0.0,"self_endowment_contribution":0.10397207708399181,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":1,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9571,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2025-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1068970,"name":"Geanne A. Freitas","orcid":null,"position":1,"is_corresponding":false},{"id":792919,"name":"MacKenzie Smith","orcid":"0000-0002-4642-1121","position":2,"is_corresponding":false},{"id":751835,"name":"Rocco D. Gogliotti","orcid":null,"position":3,"is_corresponding":false},{"id":513160,"name":"Colleen M. Niswender","orcid":"0000-0001-6009-8212","position":4,"is_corresponding":false},{"id":735153,"name":"Sheryl Anne D. Vermudez","orcid":"0000-0002-7020-8347","position":0,"is_corresponding":true}],"reference_count":80,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T02:55:21.727661Z","pmid":"40463103","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}